Dendrimers

1. Dendrimers James Scicolone ChE 702

2. What is a Dendrimer • Highly branched macromolecule • Capable of encapsulating • High loading capacity • Backbone of Carbons or Nitrogens • Monodisperse and controllable • Highly stable • Low immunogenicity and toxicity http://www.latrobe.edu.au/chemistry/staff/cfh/fig2.jpg

3. Parts of a Dendrimer http://dric.sookmyung.ac.kr/NEWS/sep03/4th%20generation%20dendrimer.jpg (05/2007)

4. Tomalia DA, Mardel K, Henderson SA, Holan G, Esfand R. Dendrimers—an enabling synthetic science to controlled organic nanostructures. In: Goddard III WA et al, editor. Handbook of nanoscience, engineering and technology. Boca Raton, FL: CRC Press; 2003.

5. Size scale of dendrimers of different generations vs. biological proteins Tomalia DA, Mardel K, Henderson SA, Holan G, Esfand R. Dendrimers—an enabling synthetic science to controlled organic nanostructures. In: Goddard III WA et al, editor. Handbook of nanoscience, engineering and technology. Boca Raton, FL: CRC Press; 2003.

6. 3-D Image http://www.wag.caltech.edu/gallery/4brdbox.gif

7. Dendrimer Synthesis • Two processes used to create dendrimers • Divergent synthesis starts at the core and branches out • Difficult to remove pure samples from side products • Convergent synthesis starts from the end groups, creating dendrons, and ends at the core • Advantage of needing less efficiency to run • Lower yield and more starting material needed • Difficult to create dendrimers in bulk

8. Divergent Synthesis http://www.fda.gov/nanotechnology/powerpoint_conversions/chbsa-nanotech-presentation06-05_files/textonly/slide10.html

9. Convergent Synthesis Lee J. W., Kim J.H., Kim Byung-Ku. Synthesis of azide-functionalized PAMAM dendrons at the focal point and their application for synthesis of PAMAM-like dendrimers, Tetrahedron Letters, 2006. 47:2683–2686

10. Encapsulation • Held by Van der Waals or dipole moments • Carrier compounds do not have to be solublized http://www2.hmc.edu/~karukstis/resdesc.htm

11. Functionalized Dendrimers • Higher generation dendrimers have a greater number of end groups that can be functionalized • Longer retention time in blood – PEG • Targeting – ability to attach to certain tissues or active sites • Imaging – Fluorescence, MRI, or X-ray • Drug Carrier • Therapeutic – used to detect disease while in body

12. Functionalized Dendrimer http://www2.hmc.edu/~karukstis/resdesc.htm

13. Functionalized Dendrimers • Hydrophobic or hydrophilic • Hydrophilic – carboxyl, PEO, or sulfonate end group • Hydrophobic – Hydrocarbons, flurocarbon, silicon end groups • Hydrophilic outer surface to the dendrimer, allowing it to penetrate aqueous regions, but inner branches could be made to be hydrophobic to allow the hydrophobic • Anionic or Cationic • Cationic dendrimers - higher cytotoxicity • net negative charge provides better membrane transport • net positive charge allows it to attach to positive receptor sites

14. Dendrimer as a drug • Antitumor, antiviral, and antibacterial agents • PAMAM and Poly(lysine) dendrimers, covalently modified with naphthyl sulfonate, which reside on the surface, have shown antiviral activity verses HIV and Herpes virus, respectively. • As antitumor drugs, dendrimers have been used primarily in photodynamic therapy. • When used as antibacterial drugs, the dendrimers adhere to the bacterial membrane and damage the anionic membrane causing the cells to burst

15. Dendrimers • Cored dendrimers, like buckyballs, able to carry larger amounts of carrier compounds, while able to be functionalized • Dendrimers as homogenous catalysts • High activity, high selectivity, good reproducibility, accessibility of the metal • Readily recovered after reactions • Candidate for ideal catalyst due to persistent and controllable nanoscale dimensions, chemically reactive surface, favorable configurations for migrating reactants, soluble, and can be easily recovered by filtration.

16. Particle formation • Process: nucleation, growth, coagulation, and flocculation • Dendrimers can alter any step of the particle formation process • Lower generation dendrimers- morphology and size control through adsorption of solubles • Higher generation dendrimers- inhibitor to crystal formation

17. Rapid, single-step preparation of dendrimer-protected silver nanoparticles through a microwave-based thermal process • Third generation poly(propyleneimine) dendrimer in AgNO3 aqueous solution • No reducing or protecting agents • Characterized UV spectra and TEM • Nobel metals provide novel properties in electronic, optical, catalytic and thermal

18. Silver nanoparticles • Dendrimer size 2.4nm • Molar ratios of 1:20, 3:20, and 9:20 dendrimer to silver • Microwave: 100% power of 600W for 8 min • Dendrimer smaller than particles • No encapsulation • Silver particles surface oxidized on PPI-G3; AgO2

19. Ag particle size vs Dendrimer molar ratio • 1:20 • 20-40nm, 25 average • Spherical • 3:20 • Over 300nm x 75nm • Spherical and rod shaped • 9:20 • 5-20nm, 10 average • Spherical

20. Particle size vs. Dendrimer molar ratio

21. Hydrothermal synthesis of hydroxyapatite nanorods in the presence of starburst dendrimers • Dendrimer, PAMAM (G 5.5), in H2O and NaOH then added to Ca ions • (NH4)2HPO4 added, precipitate collected and cleaned and hydrothermal treatment • XRD and Scherrer formula used to calculated crystal size • TEM to characterize morphology and size

22. Nanorods • Room temperature, untreated • Grain size 40nm • length 200nm x <15nm • Clongated fibers • Nanocrystal of very small size • Treated • Nanorods • 80nm with aspect ratio ~8 • Crystal nanorods with well crystallization

23. Untreated vs. Treated

24. Hydrothermal treatment vs. time • Samples treated for 3, 6, 10, and 15 hours • 3 and 6 hrs • Contained rods, aggregates, and fibers • 10 and 15 hrs • Uniform nanorods

25. Dendrimer assistance to particle formation • There are mechanisms in particle formation • The role of the dendrimer is not completely known • Much more research needs to be done to understand the process

26. Internet References: • http://dric.sookmyung.ac.kr/NEWS/sep03/4th%20generation%20dendrimer.jpg (05/2007) • http://www.che.sc.edu/centers/rcs/pizzolato/RCS%20webpage_pizzolato.htm (05/2007) • http://www.cancer.med.umich.edu/news/pro04fa05.htm (05/2007) • http://www.cancer.med.umich.edu/news/nanotech05.htm (05/2007) • http://www2.hmc.edu/~karukstis/resdesc.htm (05/2007) • http://www.fda.gov/nanotechnology/powerpoint_conversions/chbsa-nanotech-presentation06-05_files/textonly/slide10.html (05/2007) • http://kyky.essortment.com/whatisdendrime_rsnz.htm (05/2007) • http://www.ninger.com/dendrimer/ (05/2007)

27. Jackson JL, Chanzy HD, Booy FP, Drake BJ, Tomalia DA, Bauer BJ, Amis EJ. Visualization of dendrimer molecules by transmission electron (tem): staining methods and cryo-tem of vitrified solutions. Macromolecules 1998;31:6259–65. • Patri A.K., Kukowska-Latallo J.F., and Baker J.R. Jr., Targeted Drug Delivery with Dendrimers: Comparison of the Release Kinetics of Covalently Conjugated Drug and Non-Covalent Drug Inclusion Complex, Adv. Drug Deliv. Rev. , 2005, 57(15):2203-2214. • Tomalia DA, Mardel K, Henderson SA, Holan G, Esfand R. Dendrimers—an enabling synthetic science to controlled organic nanostructures. In: Goddard III WA et al, editor. Handbook of nanoscience, engineering and technology. Boca Raton, FL: CRC Press; 2003. p. 1–34. • Lee J. W., Kim J.H., Kim Byung-Ku. Synthesis of azide-functionalized PAMAM dendrons at the focal point and their application for synthesis of PAMAM-like dendrimers, Tetrahedron Letters, 2006. 47:2683–2686 • N. Malik, R. Wiwattanapatapee, R. Klopsch, K. Lorenz, H. Frey, J.W. Weener, E.W. Meijer, W. Paulus and R. Duncan, Dendrimers; relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo, J. Control. Release65 (2000), pp. 133–148. • R. Wiwattanapatapee, B. Carreno-Gomez, N. Malik and R. Duncan, Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: a potential oral delivery system?, Pharm. Res.17 (2000), pp. 991–998.

28. References • Willems and van den Wildenberg, Roadmap Report on Dendrimers, NanoRoadMap Project , 6 th Framework Programme of the European Commission , Nov. 2005. • Chung Y., and Rhee H., Internal/External Use of Dendrimer in Catalysis, Korean J. Chem. Eng ., 2004, 21(1):81-97. • Luo, Yonglan Sun, Xuping. Rapid, single-step preparation of dendrimer-protected silver nanoparticles through a microwave-based thermal process, Materials Letters. (61):1622-1624. 2007. • Zhang, Fan; Zhou, Zhuo-Hua, et. al. Hydrothermal synthesis of hydroxyapatite nanorods in the presence of starburst dendrimers, Materials Letters. (59):1422-1425. 2005. • Svenson, S. Tomalia D. Dendrimers in biomedical applications—reflections on the field. Advanced Drug Delivery Reviews57 (2005), pp. 2106-2129 • Luo, Yonglan Sun, Xuping. Rapid, single-step preparation of dendrimer-protected silver nanoparticles through a microwave-based thermal process, Materials Letters. (61):1622-1624. 2007. • Zhang, Fan; Zhou, Zhuo-Hua, et. al. Hydrothermal synthesis of hydroxyapatite nanorods in the presence of starburst dendrimers, Materials Letters. (59):1422-1425. 2005.